Beuers U.H.W.: Pathogenetic and therapeutic aspects of chronic cholestatic liver diseases

The biliary bicarbonate umbrella: We hypothesized that biliary bicarbonate secretion is essential for protection of human biliary epithelia against uncontrolled influx of nonpolarized glycine-conjugated bile acids (Beuers et al., Hepatology 2010; Hohenester et al. Hepatology 2012). Genetic polymorphisms may contribute to weakening of the biliary bicarbonate umbrella leading to chronic cholangiopathies like primary biliary cirrhosis, primary sclerosing cholangitis, cystic fibrosis-associated liver disease or posttransplant biliary strictures. Pharmacological stabilization of the bicarbonate umbrella with bile salts (e.g., ursodeoxycholate, norursodeoxycholate) or nuclear receptor agonists (e.g., obeticholate) represents a potential therapeutic strategy for these disorders. Itch in cholestasis: Itch is a major burden for patients with cholestatic disorders. Its pathogenesis is unknown. We recently identified autotaxin (ATX) and its product, lysophosphatidic acid (LPA), a pruritogen in rodents, in serum of patients with cholestatic itch at higher concentrations than in controls and found a striking association with itch intensity (Kremer et al., Gastroenterology 2010) and treatment
response (Kremer et al., Hepatology 2012). We also found that the most potent antipruritic agent, the pregnane-X receptor (PXR) agonist rifampicine, impairs ATX expression by PXR-dependent mechanisms possibly explaining its beneficial effect in patients at least in part (Kremer, van Dijk et al. Hepatology 2012). Further understanding of the role of ATX/LPA in cholestatic itch may allow development of novel therapeutic strategies for management of itch (for review: Beuers et al. Hepatology 2014, epub). IgG4-associated cholangitis (IAC) and IgG4-related systemic disease: IAC is a recently defined autoimmune bile duct disorder which is often associated with autoimmune pancreatitis or other systemic manifestations of IgG4-related systemic disease. IAC has a good prognosis when adequately diagnosed and treated. The pathogenesis of this corticosteroid-responsive disorder is completely unknown. In clinical practice, it is challenging to differentiate IAC, cholangiocarcinoma (CCA) or primary sclerosing cholangitis (PSC) as these disorders may show comparable features in serum biochemistry and cholangiography. Bile duct cytology / histology is often of limited reliability for the
diagnosis. IgG4 serum levels may be elevated in all these disorders. We recently succeeded by use of a novel next generation sequencing technique in unraveling highly abundant IgG4+ B cell receptor (BCR) clones in blood and tissue of patients with active IAC (but not PSC or CCA), which disappear upon corticosteroid treatment (Maillette de Buy Wenniger, Doorenspleet et al. Hepatology 2013). Our data strongly suggest that specific B cell responses are pivotal to the pathogenesis of IAC. In support of our concept, we most recently identified "blue collar work" as a potential risk factor for development of IgG4-related disease in two independent cohorts of patients with IgG4-related systemic disease (Maillette de Buy Wenniger, Curver, Beuers, Hepatology 2014, epub). Our next aims are to define the antigens against which IgG4 are directed in IAC and to better understand the pathophysiological role of IgG4 in IgG4-related systemic disease. Severe persistent hepatocellular secretory failure (PHSF): We recently identified the pregnane X receptor (PXR) agonist rifampicin as a potent drug to effectively treat severe persistent hepatocellular secretory failure, a rare disorder induced by
drugs, toxins or transient bile duct obstruction and associated with severe progressive jaundice (bilrubine > 255 umol/l) after removal of the trigger. We try to elucidate the molecular mechanisms involved in PHSF and its reversal induced by the PXR agonist rifampicin (van Dijk et al. submitted). Clinical therapeutic trials 2014: - Obeticholate in primary biliary cirrhosis, - Budesonide in primary biliary cirrhosis, - Norursodeoxycholate in primary sclerosing cholangitis, - Diagnosis and treatment of IgG4-associated cholangitis, - Rifampicin in severe persistent hepatocellular secretory failure, - A PPAR alpha/delta agonist in nonalcoholic steatohepatitis (NASH)